Profile of the breast cancer susceptibility marker rs4245739 identifies a role for miRNAs

OBJECTIVE: To determine the influence of the single nucleotide polymorphism (SNP) rs4245739 on the binding and expression ofmicroRNAs and subsequent MDM4 expression and the correlation of these factors with clinical determinants of ER-negativebreast cancers. METHODS: FindTar and miRanda were used to detect the manner in which potential microRNAs are affected by the SNPrs4245739-flanking sequence. RNA sequencing data for ER-negative breast cancer from The Cancer Genome Atlas (TCGA) wereused to compare the expression of miR-184, miR-191, miR-193a, miR-378, and MDM4 in different rs4245739 genotypes. RESULTS: Comparison of ER-negative cancer patients with and without the expression of miR-191 as well as profile microRNAs(miR-184, miR-191, miR-193a and miR-378 altogether) can differentiate the expression of MDM4 among different rs4245739genotypes. Although simple genotyping alone did not reveal significant clinical relationships, the combination of genotyping andmicroRNA profiles was able to significantly differentiate individuals with larger tumor size and lower number of involved lymphnodes (P < 0.05) in the risk group (A allele). CONCLUSIONS: We present two novel methods to analyze SNPs within 3′UTRs that use: (i) a single miRNA marker expression and(ii) an expression profile of miRNAs predicted to bind to the SNP region. We demonstrate that the application of these twomethods, in particular the miRNA profile approach, permits detection of new molecular and clinical features related to thers4245739 variant in ER-negative breast cancer

Adiposity, telomere length and telomere attrition in midlife: the 1946 British Birth Cohort.

BACKGROUND: Obesity has been linked with shorter telomere length, both of which have been implicated in ageing, but the impact of early life adiposity on telomere length is unclear. METHODS: We included 2,479 participants from the MRC National Survey of Health and Development with measurements of body mass index (BMI), waist and hip circumference and leukocyte telomere length (LTL) at age 53, of whom 1,000 had second measurements at age 60-64. Relative LTL was measured with rt-PCR. Linear regression was performed to investigate associations between adiposity and LTL. BMI from childhood through adulthood was used to assess adiposity across the life course. RESULTS: We found no cross-sectional associations between adiposity measures and LTL at age 53 or 60-64. Longitudinally, each unit gain in waist circumference weakly corresponded with a 0.06% (95% CI: -1.31 to 0.10) LTL decrease annually, with association approaching statistical significance (P=0.09). Being overweight at age 6 and 15 corresponded to a non-significant shorter LTL at age 53 and they are associated with 2.06% (95% CI: 0.05 to 4.08%) and 4.26% (1.98 to 6.54%) less LTL attrition in midlife, respectively compared to those who were not overweight. CONCLUSION: There is a weak indication that greater telomere loss was seen with greater concurrent BMI gain. Adolescent overweight corresponded to shorter telomeres in midlife, albeit weakly, and with less subsequent attrition. Our findings point toward potential pathways which may link adiposity and ageing outcomes

Investigating the associations between adiposity, life course overweight trajectories, and telomere length

Obesity may accelerate ageing through chronic inflammation. To further examine this association, we assessed current adiposity, adiposity at early adulthood and life course overweight trajectories in relation to leukocyte telomere length (LTL). We included a total of 7,008 nationally representative U.S. residents and collected information on objectively measured body mass index (BMI), waist circumference and percent body fat. BMI at age 25 and overweight trajectories were assessed using self-reported history. Leukocyte telomere length (LTL) relative to a standard DNA reference (T/S ratio) was quantified by polymerase chain reaction (PCR). Linear regression models were used to examine the difference in LTL across adiposity measures at examination, BMI at age 25, and overweight trajectories. A 0.2% decrease in telomere length (95% CI: -0.3 to -0.07%) was observed for every kg/m2 increase in BMI, whereas a unit increase in waist circumference (cm) and percent body fat contributed to a 0.09% and 0.01% decrease in LTL, respectively. Higher BMI and being obese at age 25 contributed to lower LTL at older ages. Associations between weight loss through life course and LTL were observed, which further marked the importance of life course adiposity dynamics as a determinant of ageing

The Relationship of Early-Life Adversity With Adulthood Weight and Cardiometabolic Health Status in the 1946 National Survey of Health and Development

OBJECTIVE: Evidence linking early-life adversity with an adverse cardiometabolic profile in adulthood is equivocal. This study investigates early-life adversity in relation to weight and cardiometabolic health status at ages 60 to 64 years. METHODS: We included 1059 individuals from the 1946 National Survey of Health and Development. Data on adversity between ages 0 to 15 years were used to create a cumulative childhood psychosocial adversity score and a socioeconomic adversity score. Cardiometabolic and weight/height data collected at ages 60 to 64 years were used to create four groups: metabolically healthy normal weight, metabolically unhealthy normal weight, metabolically healthy overweight/obese, and metabolically unhealthy overweight/obese. Associations between the two exposure scores and weight/health status were examined using multinomial logistic regression, with adjustment for sex and age at the outcome visit. RESULTS: Sixty-two percent of normal-weight individuals were metabolically healthy, whereas only 34% of overweight/obese individuals were metabolically healthy. In a mutually adjusted model including both exposure scores, a psychosocial score of ≥3 (compared with 0) was associated with increased risk of being metabolically unhealthy (compared with healthy) in both normal-weight adults (relative risk = 2.49; 95% confidence interval = 0.87–7.13) and overweight/obese adults (1.87; 0.96–3.61). However, the socioeconomic adversity score was more strongly related to metabolic health status in overweight/obese adults (1.60; 0.98–2.60) than in normal-weight adults (0.95; 0.46–1.96). CONCLUSIONS: Independently of socioeconomic adversity, psychosocial adversity in childhood may be associated with a poor cardiometabolic health profile, in both normal-weight and overweight/obese adults. Childhood adversity might cause obesity via the adoption of unhealthy behaviors. It might also cause poor cardiometabolic health, either via obesity or via another pathway (e.g., altered stress response). Robson et al. found that childhood adversity was associated with poor cardiometabolic health at ages 60 to 64 years, in both normal-weight and overweight/obese adults. Further research is needed to understand the mechanisms by which childhood adversity might affect cardiometabolic health without necessarily increasing body weight

Smoking, second-hand smoke exposure and smoking cessation in relation to leukocyte telomere length and mortality

OBJECTIVES: To investigate the link between smoking exposure, telomere length and mortality, with emphasis on second-hand smoke (SHS) exposure and the duration of smoking cessation. RESULTS: A total of 1,018 participants died during follow-up (mean: 10.3 years). A 50 base-pair decrease in LTL was shown among cotinine-confirmed current versus never smokers. The 90th quantile of LTL decreased with increasing cotinine among never smokers, indicating a role of SHS. Longer telomeres with smoking cessation were indicated but limited to a 3-16 year period of abstaining smoking. When assessing mortality, we observed a lower risk of all-cause death for the second quintile compared to the first among never smokers (HR: 0.67, 95% CI: 0.52-0.87), and a higher risk was found among current smokers (HR: 1.89, 1.19-2.92). MATERIALS AND METHODS: We studied 6,456 nationally representative U.S. respondents with mortality follow-up through to 31 December 2011. Smoking status was assessed by interviews and cotinine levels. Relative leukocyte telomere length (LTL) was quantified by polymerase chain reaction (PCR). Multivariable linear regression was performed to examine LTL by smoking exposure, adjusted for age, sex, race/ethnicity, socioeconomic status, education, body mass index, alcohol consumption, and physical activity. We further estimated the association of LTL with cotinine levels using quantile regression, and with smoking cessation dynamics. Cox regression was used to estimate mortality by smoking status and LTL. CONCLUSION: Our findings indicated a complex association between smoking, telomere length, and mortality. LTL alterations with SHS and smoking cessation warrant further investigation for translation to public health measures

Associations of medical conditions, lifestyle and unintentional weight loss in early old age: The 1946 British Birth Cohort

Background: Unintentional weight loss in older people has been linked to increased risk of mortality. We aimed to investigate common medical conditions and lifestyle factors, including body fat distribution, as potential determinants of recent and prospective unintentional weight loss in early old age. / Methods: From the Medical Research Council (MRC) National Survey of Health and Development (NSHD), we included a total of 2234 study members aged 60–64 with information on unintentional weight loss in 2006–2010. Of these, 2136 also had information on unintentional weight loss recorded in 2015. Logistic regression was conducted to examine the associations between medical conditions, lifestyle, and body fat distribution at age 60–64 and unintentional weight loss at age 60–64 and 69. / Results: A total of 109 of 2234 study members had unintentional weight loss at ages 60–64, and 166 of 2136 at age 69. Never smoking was associated with lower risk of unintentional weight loss at age 60–64 (OR = 0.29, 95%CI = 0.12–0.68 compared to current smokers), and this association remained when adjusted for other determinants. Greater waist-hip ratio (OR = 0.95, 95%CI = 0.91–0.99) and body fat-lean mass ratio (OR = 0.96, 95%CI = 0.94–0.99) were associated with less likelihood of unintentional weight loss at age 60–64. Never smoking and greater hip circumference at age 60–64 were associated with lower odds of unintentional weight loss at age 69. / Conclusions: Smoking status and body fat distribution may help identify those at risk of unintentional weight loss in early old age. Their benefit in interventions to prevent age-associated weight loss needs to be further investigated

Parental age and offspring leukocyte telomere length and attrition in midlife: Evidence from the 1946 British birth cohort

BACKGROUND: There is evidence that paternal age may influence offspring telomere length, but the joint effects of father's and mother's age are unclear. We evaluated whether parental ages, individually and jointly, were associated with offspring telomere length and shortening. METHODS: We included 2305 British birth cohort participants with measured leukocyte telomere length (LTL) at age 53, among whom 941 had a second measurement at age 60-64. Linear regressions were performed to assess the associations of father's and mother's age at birth and the parental age gap, i.e. the difference between maternal and paternal age with LTL and LTL change. RESULTS: A one year increase in father's age corresponded to a 0.26% (95% CI: 0.04-0.47%) increase in offspring LTL at age 53 in the sex-adjusted model. No association was observed for mother's age. Associations of father's or mother's age with offspring LTL at age 53 went to opposite directions when both parental ages were included together. For the difference in parental age, every year that fathers were older than mothers corresponded to a 0.94% (95% CI, 0.38-1.50%) increase in LTL at age 53 after adjustment for potential confounders. Neither parental ages nor the difference in parental ages were correlated with LTL change. CONCLUSION: There was a joint effect of parental ages on offspring telomere length, further denoting a complex role of reproductive age in offspring health and ageing